Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SDZ PSC 833 ([3'-keto-Bmt1]-[Val2]-cyclosporin) is a P-glycoprotein-mediated multidrug resistance modulator currently undergoing clinical trials. SDZ PSC 833 modulates not only antitumor activity but also tissue distribution of doxorubicin in mice. Since protein binding in plasma/serum and distribution to blood cells are important factors affecting the tissue distribution and excretion of drugs, we investigated the effect of SDZ PSC 833 on serum protein binding and distribution to blood cells of doxorubicin, vincristine and etoposide in vitro. Unbound fractions in serum and fractions distributed to blood cells of either [14C]doxorubicin, [3H]vincristine or [3H]etoposide were determined using serum and blood obtained from mice and healthy volunteers. Effects of SDZ PSC 833 at 3 microg/ml, which was an achievable concentration in a clinical trial of SDZ PSC 833, on protein binding and distribution of the drugs to blood cells were negligible in mouse and human blood in vitro. The absence of interaction between PSC 833 and the anticancer drugs in protein binding and distribution to blood cells suggested the existence of other mechanisms. Possible interactions are speculated to be inhibition of P-glycoprotein function contributing to drug excretion and tissue distribution and inhibition of drug metabolism mediated by cytochrome P450 3A.
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PMID:Effect of SDZ PSC 833 ([3'-keto-Bmt1]-[Val2]-cyclosporin) on serum protein binding and distribution to blood cells of doxorubicin, vincristine and etoposide in vitro. 918 Mar 96

Itraconazole strongly interacts with some drugs metabolized by cytochrome P450 3A4, for example, felodipine and lovastatin, by inhibiting their metabolism. A concomitant use of itraconazole increases the serum concentrations of digoxin, although digoxin is excreted mainly unchanged in urine. To reveal the mechanism of the itraconazole-digoxin interaction, the effect of itraconazole on the serum concentrations and urinary excretion of digoxin was studied. Ten healthy volunteers in a double-blind, randomized, two-phase crossover study received either 200 mg itraconazole or placebo orally once a day for 5 days. On day 3, each volunteer ingested a single 0.5-mg oral dose of digoxin. The serum concentrations of digoxin and its excretion into urine as well as plasma concentrations of itraconazole were determined up to 72 hours after dosing. The mean area under the serum digoxin concentration-time curve, AUC(0-72), was approximately 50% higher (P < 0.001) during the itraconazole phase than during the placebo phase. In addition, the renal clearance of digoxin decreased about 20% (P < 0.01) by itraconazole. The increases in digoxin Cmax and T(1/2) by itraconazole were not statistically significant. The decreased renal clearance of digoxin during the itraconazole phase partially explains increased concentrations of digoxin during their concomitant use and may be caused by the inhibition of P-glycoprotein-mediated digoxin secretion in the renal tubular cells.
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PMID:Itraconazole decreases renal clearance of digoxin. 942 Oct 99

A strong overlap between P-glycoprotein (Pgp) and cytochrome P450 3A (CYP3A) substrates and modulators has been reported. To test the hypothesis that CYP3A and Pgp are coordinately regulated, we examined the effects of known inducers of CYP3A (triacetyloleandomycin, rifampicin, dexamethasone, pregnenolone 16alpha-carbonitrile) on Pgp expression in rat liver. We also investigated the gender-specific expression of Pgp and compared its response to dexamethasone between male and female rats. In male rats, western blot analyses showed that rifampicin and dexamethasone caused 50% and 5-fold increases in Pgp levels, respectively. RNase protection assays using gene-specific probes for the three Pgp isoforms revealed a 3-fold increase in mdr2 mRNA levels after dexamethasone administration and a 2-fold increase following rifampicin treatment. Triacetyloleandomycin and pregnenolone 16alpha-carbonitrile had no effect on Pgp expression and mRNA levels. We also observed that the basal level of Pgp was 40% lower in male rats than in females and that mdr2 mRNA levels in male rats were one-half those in females. As opposed to the results in male rats, dexamethasone reduced Pgp expression by approximately 60% and caused a 30% decrease in mdr2 mRNA levels in female rats. Mdr1a was not affected and mdr1b was not detected in female or male rats. We conclude that, at the dosage regimen used, CYP3A and Pgp responses to CYP3A inducers are regulated independently in rat liver. In addition, this study shows that Pgp expression and regulation are gender specific.
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PMID:Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. 951 72

K02 (morpholine-urea-Phe-Hphe-vinylsulfone), a newly developed peptidomimetic, acts as a potent cysteine protease inhibitor, especially of cathepsins B and L (which are associated with cancer progression) and cruzain (a cysteine protease of Trypanosoma cruzi, which is responsible for Chagas' disease). Here we investigated features of the disposition of K02 using in vitro systems, characterizing the interaction of the drug with human cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), a mediator of multidrug resistance (MDR) to cancer chemotherapy and a countertransporter in the intestine that limits oral drug bioavailability. P-gp functions as an ATP-dependent drug efflux pump to reduce intracellular cytotoxic concentrations. An HPLC assay was developed to analyze K02 and its metabolites formed in human liver microsomes. Three major primary metabolites were determined by LC/MS/MS to be hydroxylated products of the parent compound. A rabbit anti-CYP3A polyclonal antibody (200 microl antibody/mg microsomal protein) produced 75-94% inhibition of the formation of these three hydroxylated metabolites. Ketoconazole (5 microM), a selective CYP3A inhibitor, produced up to 75% inhibition, whereas other CYP-specific inhibitors, i.e. quinidine (CYP2D6), 7,8-benzoflavone (CYP1A2), and sulfaphenazole (CYP2C9), showed no significant effects. An identical metabolite formation profile for K02 was observed with cDNA-expressed human CYP3A4 (Gentest). These data demonstrate that K02 is a substrate for CYP3A. Formation of 1'-hydroxymidazolam, the primary human midazolam metabolite, was markedly inhibited by K02 via competitive processes, which suggests the potential for drug-drug interactions of K02 with other CYP3A substrates. K02 significantly inhibited the photoaffinity labeling of P-gp with azidopine and LU-49888, a photoaffinity analogue of verapamil. Transport studies with [14C]K02, using MDR1-transfected Madin-Darby canine kidney cell monolayers in the Transwell system, demonstrated that the basolateral-to-apical flux of K02 across MDR1-transfected Madin-Darby canine kidney cells was markedly greater than the apical-to-basolateral flux (ratio of 63 with 10 microM [14C]K02). This suggests that K02 is also a P-gp substrate. These studies are important for formulating strategies to increase the absorption and/or decrease the elimination of K02 and to optimize its delivery to malignant cells and parasite-infected host cells.
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PMID:Overlapping substrate specificities of cytochrome P450 3A and P-glycoprotein for a novel cysteine protease inhibitor. 953 25

Digoxin, a cardiac glycoside, is a substrate of the multidrug transporter P-glycoprotein (Pgp), and in rats has also been identified as a substrate for cytochrome P450 3A (CYP3A). Ketoconazole, an antifungal agent, was shown to inhibit Pgp in a multidrug-resistant cell line, and is known to be a potent inhibitor of CYP3A. Here, we determined the effects of ketoconazole on digoxin absorption and disposition in rats. Digoxin was administered intravenously or orally with or without a concomitant oral dose of ketoconazole. When given intravenously, digoxin AUC increased from 93 +/- 22 to 486 +/- 26 microg x h/l with ketoconazole administration. Similarly, ketoconazole raised the AUC of orally administered digoxin from 63 +/- 17 to 411 +/- 50 microg x h/l. Concomitant ketoconazole administration prolonged digoxin elimination, yielding a nonlinear pharmacokinetic profile. Using time-averaged values, digoxin bioavailability increased from 0.68 +/- 0.18 to 0.84 +/- 0.10, while mean absorption time was reduced from 1.1 +/- 0.4 to 0.3 +/- 0.1 h. Thus, in rats, ketoconazole increases digoxin plasma concentrations, rate of absorption and bioavailability. Although the effects of ketoconazole on AUC could be explained by inhibition of both CYP3A and Pgp, which cannot be differentiated in this study, the decreased mean absorption time can only be explained by inhibition of Pgp in the intestine.
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PMID:Effects of ketoconazole on digoxin absorption and disposition in rat. 965 17

Antiprogestins represent a relatively new and promising class of therapeutic agents that could have significant impact on human health and reproduction. In the present work, the pharmacodynamics, pharmacokinetics, and metabolism of mifepristone (MIF), lilopristone (LIL), and onapristone (ONA) in humans are reviewed, and characteristics bearing important clinical implications are discussed. Although MIF has gained notoriety as an "abortion pill," antiprogestins may more importantly prove effective in the treatment of endometriosis, uterine leiomyoma, meningioma, cancers of the breast and prostate, and as contraceptive agents. MIF pharmacokinetics display nonlinearities associated with saturable plasma protein (alpha 1-acid glycoprotein, AAG) binding and characterized by lack of dose dependency for parent drug plasma concentrations (for doses greater than 100 mg) and a zero-order phase of elimination. LIL and ONA pharmacokinetics are less well characterized but ONA does not appear to bind AAG and displays a much shorter t1/2 than the other agents. The three antiprogestins are substrates of cytochrome P450 (CYP) 3A4, an enzyme exceedingly important in human xenobiotic metabolism. Even more implicative of likely drug-drug interactions subsequent to their long-term administration are recent data from our laboratory indicating that they inactivate CYP3A4 in a cofactor- and time-dependent manner, suggesting that complexation and induction of the enzyme may occur in vivo via protein stabilization. Moreover, it has been demonstrated that MIF increases CYP3A4 mRNA levels in human hepatocytes in primary culture, indicative of message stabilization and/or transcriptional activation of CYP3A4 expression. Finally, MIF has also been shown to inhibit P-glycoprotein function. Whether LIL and ONA share these latter two characteristics with MIF has not yet been determined but they illustrate properties that, in addition to diminished antiglucocorticoid activities and altered pharmacokinetic characteristics, warrant consideration during the development of these and never antiprogestational agents.
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PMID:Antiprogestin pharmacodynamics, pharmacokinetics, and metabolism: implications for their long-term use. 969 76

The metabolism of valspodar (PSC 833; PSC), which is developed as a multidrug resistance-reversing agent, was investigated to assess the potential for drug-drug interactions and the pharmacological activity of major metabolites. The primary metabolites of PSC produced by human liver microsomes were monohydroxylated, as revealed by LC/MS. The major site of hydroxylation was at amino acid 9, resulting in M9, as determined by cochromatography with synthetic M9. Dihydroxylated and N-demethylated metabolites were also detected. PSC metabolism in two human livers exhibited KM values of 1.3-2.8 microM. The intrinsic clearance was 9-36 ml/min/kg of body weight. PSC biotransformation was cytochrome P450 (CYP or P450) 3A dependent, based on chemical inhibition and on metabolism by Chinese hamster ovary cells expressing CYP3A. Ketoconazole was a competitive inhibitor (Ki = 0.01-0.04 microM). The inhibition by 27 compounds, including four antineoplastic agents, corresponded to the inhibitory potentials of these compounds toward CYP3A. For vinblastine, paclitaxel, doxorubicin, and etoposide, the IC50 values were 5, 12, 20, and 150 microM, respectively. M9 was also an inhibitor, with a lower apparent affinity for CYP3A (IC50 = 21 microM), compared with that of PSC. M9 was also less active as a multidrug resistance-reversing agent. M9 demonstrated low potency in sensitizing resistant cells to paclitaxel and was a poor inhibitor of rhodamine-123 efflux from paclitaxel-resistant cells. In addition, compared with PSC, a higher concentration of M9 was needed to compete with the photoaffinity labeling of P-glycoprotein. Conversely, PSC inhibited only reactions catalyzed by CYP3A, including cyclosporine A metabolism (IC50 = 6.5 microM) and p-hydroxyphenyl-C3'-paclitaxel formation (Ki = 1.2 microM). Thus, PSC behaves in a manner very similar to that of other cyclosporines, and a comparable drug-drug interaction profile is expected.
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PMID:The multidrug resistance modulator valspodar (PSC 833) is metabolized by human cytochrome P450 3A. Implications for drug-drug interactions and pharmacological activity of the main metabolite. 969 96

The anti-HIV protease inhibitors represent a new class of agents for treatment of HIV infection. Saquinavir, ritonavir, indinavir, and nelfinavir are the first drugs approved in this class and significantly reduce HIV RNA copy number with minimal adverse effects. They are all substrates of cytochrome P450 3A4, and are incompletely bioavailable. The drug transporting protein, P-glycoprotein (P-gp), which is highly expressed in the intestinal mucosa, could be responsible for the low oral bioavailability of these and other drugs which are substrates for this transporter. To determine whether these protease inhibitors are modulators of P-gp, we studied them in cell lines which do and do not express P-gp. Saquinavir, ritonavir and nelfinavir significantly inhibited the efflux of [3H]paclitaxel and [3H]vinblastine in P-gp-positive cells, resulting in an increase in intracellular accumulation of these drugs. However, similar concentrations of indinavir did not affect the accumulation of these anticancer agents. In photoaffinity labeling studies, saquinavir and ritonavir displaced [3H]azidopine, a substrate for P-gp, in a dose-dependent manner. These data suggest that saquinavir, ritonavir, and nelfinavir are inhibitors and possibly substrates of P-gp. Because saquinavir has a low bioavailability, its interaction with P-gp may be involved in limiting its absorption.
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PMID:Interaction of anti-HIV protease inhibitors with the multidrug transporter P-glycoprotein (P-gp) in human cultured cells. 980 61

Involvement of the cytochrome P450 (CYP) 3A subfamily in the metabolism of vincristine is well established. However, information is limited regarding vincristine's drug interaction profile. All the substrates and inhibitors of CYP3A4 such as the azole antifungals (itraconazole, ketoconazole), cyclosporine, isoniazid, and nifedipine have very high propensity to interfere with vincristine metabolism. The proposed mechanism is most likely attributed to either inhibition of 3A4 enzymes or blockade of P-glycoprotein pumps. These interactions are clinically significant and can lead to severe vincristine toxicity if not detected. Although case reports discussed here exclusively involve vincristine, it is important to assume that all vinca alkaloids interact in the same manner until proved otherwise, because they share similar metabolism pathways.
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PMID:Pharmacokinetic drug interactions of vinca alkaloids: summary of case reports. 985 31

We examined the effects of the administration of different bile acids on in vivo hepatic murine cytochrome P450 (CYP) content, nicotinamide adenine dinucleotide phosphate (NADPH)-CYP-reductase, and individual mixed-function oxidases (MFOs). Neither CYP level nor reductase were appreciably affected by single intraperitoneal administration of taurodeoxycholic acid (TDCA) (12.2 or 24.4 mg x kg(-1) bw). MFO to various isoenzymes were slightly reduced 24 hours after treatment. Taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA) both induced CYP, reductase, and MFOs. CYP3A1/2-linked activity (i.e., testosterone 6beta-hydroxylase, and N-demethylation of aminopyrine) in a dose-dependent fashion was enhanced ( approximately 2-3-fold). CYP2E1- (hydroxylation of p-nitrophenol), CYP1A2-(O-demethylation of methoxyresorufin), CYP2A1/2- and CYP2B1/2-(6alpha-hydroxylase), and CYP2B9- (16alpha-hydroxylase) dependent MFOs, as well as 7alpha-, 16beta-, 2alpha-, and 2beta-hydroxylations, were all significantly induced by THDCA. Apart from alkoxyresorufin metabolism and a modest CYP2E1 increase, TUDCA behaved like THDCA. A generalized induction was also recorded after ursodeoxycholic acid (UDCA) administration. THDCA and TDCA did not show substantial differences in the N-demethylation of aminopyrine when different species (rat vs. mouse) and administration route (intraperitoneal vs. intravenous) were compared. Results on the most affected isoenzymes, CYP3A1/2 (THDCA, TUDCA, and UDCA) and CYP2E1 (UDCA), were sustained by means of Western immunoblotting. CYP3A induction was paralleled by a corresponding increase in mRNA. These data could partially explain the therapeutic mechanism of UDCA, TUDCA, and THDCA in chronic cholestatic liver disease. CYP3A induction, which is linked to P-glycoprotein (Pgp) family overexpression, may enhance hepatic metabolism, transport, and excretion of toxic endogenous lipophilic bile acids.
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PMID:Bile acid structure and selective modulation of murine hepatic cytochrome P450-linked enzymes. 1046 80


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